Evaluation of the Potential Pharmacokinetic Interactions Between Probe Drugs in the Geneva Phenotyping Cocktail

Sponsor

Jules Desmeules (Other)

Overall Status

Completed

CT.gov ID

NCT02391688

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Phenotyping is an approach largely used for the evaluation of the activity of cytochromes and transporters in vivo. It consists of the administration of probe substances metabolised by a specific cytochrome or transported by P-glycoprotein (P-gp) for example, followed by the determination of a metabolic ratio or the evaluation of the plasmatic or urinary concentrations of the probe substances. The administration of a cocktail containing several probe substances allows the simultaneous evaluation of the activity of several cytochromes and P-gp in a single test.

When a cocktail approach is used it is important to make sure that no drug-drug interactions occur between the probes within the cocktail. The validation of the lack of interactions, which is the aim of the study, consists of demonstrating that there is no difference in the pharmacokinetic parameters and/or metabolic ratios when a probe is administered alone or as part of the cocktail. The Geneva cocktail consists of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam and fexofenadine for the simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CAP2C19, CYP2D6, CYP3A4 and P-gp, respectively.

Probe and metabolite concentrations will be measured in capillary blood using a dried blood spot (DBS) analysis. To further facilitate sampling, a new simple device will be used to ensure the precision of capillary blood collection.

Condition or Disease	Intervention/Treatment	Phase
Drug Interaction	Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam Drug: Bupropion Drug: Fexofenadine	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Study Start Date :

Nov 1, 2014

Actual Primary Completion Date :

Apr 1, 2015

Actual Study Completion Date :

Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment A Oral intake of: caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg	Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam
Experimental: Treatment B Oral intake of: fexofenadine 25 mg	Drug: Fexofenadine
Experimental: Treatment C Oral intake of: bupropion 20 mg	Drug: Bupropion
Experimental: Treatment D Oral Intake of Geneva cocktail (A+B+C): caffeine 50 mg dextromethorphan 10 mg omeprazole 10 mg flurbiprofen 10 mg midazolam 1 mg fexofenadine 25 mg bupropion 20 mg	Drug: Caffeine, omeprazole, flurbiprofen, dextromethorphan, midazolam Drug: Bupropion Drug: Fexofenadine

Outcome Measures

Primary Outcome Measures

Area under the capillary blood concentration-time curve (AUC) of caffeine [0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of caffeine AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of dextromethorphan [0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of dextromethorphan AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of flurbiprofen [0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of flurbiprofen AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of midazolam [0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of midazolam AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of omeprazole [0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of omeprazole AUC when treatment A or D is administered
Area under the capillary blood concentration-time curve (AUC) of fexofenadine [0, 0.5, 1, 2, 3, 4, 6, 8 hours post treatment B or D]
Comparison of fexofenadine AUC when treatment B or D is administered
Area under the capillary blood concentration-time curve (AUC) of bupropion [0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D]
Comparison of bupropion AUC when treatment C or D is administered

Secondary Outcome Measures

Metabolic ratio (MR) of paraxanthine blood concentration /caffeine blood concentration [0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of paraxanthine/caffeine MRs between treatment A and D
Metabolic ratio (MR) of dextrorphan blood concentration /dextromethorphan blood concentration [0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of dextrorphan/dextromethorphan MRs between treatment A and D
Metabolic ratio (MR) of 4-hydroxyflurbiprofen blood concentration /flurbiprofen blood concentration [0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of 4-hydroxyflurbiprofen/flurbiprofen MRs between treatment A and D
Metabolic ratio (MR) of 1-hydroxymidazolam blood concentration /midazolam blood concentration [0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of 1-hydroxymidazolam/midazolam MRs between treatment A and D
Metabolic ratio (MR) of 5-hydroxyomeprazole blood concentration /omeprazole blood concentration [0.5, 1, 2, 3, 4, 6, 8 hours post treatment A or D]
Comparison of 5-hydroxyomeprazole/omeprazole MRs between treatment A and D
Metabolic ratio (MR) of 4-hydroxybupropion blood concentration /bupropion blood concentration [0.5, 1, 2, 3, 4, 6, 8, 12, 24 hours post treatment C or D]
Comparison of 4-hydroxybupropion/bupropion MRs between treatment C and D
Number of adverse events [at each drug administration day]

Other Outcome Measures

Correlation of drug concentrations (ng/ml) in DBS obtained with two sampling techniques for all administered drugs [0.5, 1, 2, 3, 4, 6, 8 hours post treatment A, B, C and D]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy volunteers aged from 18 to 60 years
BMI between 18 and 27
Understanding of French language and able to give a written inform consent.

Exclusion Criteria:

smoker
pregnant women
taking drugs which alter cytochrome P450 (CYP) activity
renal or hepatic impairment
medical history of chronic alcoholism or abuse of psychoactive drugs
liver transplantation
sensitivity to any of the drugs used
Alteration of hepatic tests, more than 2x normal (aspartate transaminase >100U/L ; alanine transaminase >100 units/L ; gamma-glutamyl transferase >80 units/L ; bilirubin